Abstract
The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients.
This study examined the effect of cigarette smoke (CS) on ET receptor A (ETA) and B (ETB) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences.
CS extract (CSE) increased ETA and ETB expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ETA antagonist BQ123 and the ETB antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ETA and ETB than those of nonsmoker patients.
These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.
- Bosentan
- cigarette smoke
- endothelin receptor
- human pulmonary artery smooth muscle cells
- precision-cut lung slice
Footnotes
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Support Statement
This work was supported by grants SAF2008-03113 (J. Cortijo), SAF2009-08913 (E.J. Morcillo), and CIBERES (CB06/06/0027) from the Ministry of Science and Innovation and Health Institute Carlos III of the Spanish Government, and research grants (Prometeo/2008/045 and Emerging Groups GE-029/10) from the Regional Government (“Generalitat Valenciana”).
Statement of Interest
None declared.
- Received February 4, 2011.
- Accepted July 25, 2011.
- ©ERS 2012